Highlights d 2-and 3-antigen AND or NOT logic gates improve tumor discrimination of CAR T cells d All transmembrane antigen combination pairs and triples are computationally screened d Combinatorial antigens that outperform current clinical CAR T cells are predicted d Adding antigens improves precision at the cost of recall; 2-3 is optimal
Susceptible adults (n Å 105) were enrolled into a randomized double-blind study of rimantadine treatment of experimental influenza A infection. Subjects were cloistered for 8 days and challenged with a rimantadine-sensitive strain of influenza A H1N1 virus at the end of the first day. Fortyeight hours after challenge and for 8 days, 54 subjects received placebo and 51 received rimantadine (100 mg orally, twice a day). Symptoms, signs, and pathophysiologies were monitored. Nine subjects were not infected. Seventeen subjects (38%) in the rimantadine and 26 (53%) in the placebo group became ill. A beneficial effect of rimantadine was documented for virus shedding, symptom load, and sinus pain. Rimantadine had no effect on nasal patency, mucociliary clearance, nasal signs, or on symptoms and signs of otologic complications. These results do not support a preventive effect of rimantadine on the development of otologic manifestations of influenza A infection in adults. Otitis media (OM) is characterized by the presence of in-Experimental respiratory virus infection of human adults has been used to study the pathogenesis of the virus infection and flammation within the middle ear and is second in frequency of diseases affecting infants and children only to upper respiraits complications. In two studies, experimental influenza A virus infection caused sequential otologic complications, intory tract infections (URIs) [1]. Established OM is refractory to current methods of medical treatment and can persist for cluding eustachian tube dysfunction (80%), middle ear underpressures (70%), and OM (20%) after the initial expression of weeks, months, or even years [2]. Epidemiologic studies show that ú50% of new episodes of OM are temporally associated the signs and symptoms of the primary infection [7,8]. These observations suggest a causal pathway leading from virus infecwith a viral URI, and experimental studies document a causal relationship between the two diseases [3 -8]. Our understandtion to OM via the intermediate development of eustachian tube dysfunction and middle ear underpressures. This experimental ing of OM pathogenesis predicts a temporal delay between the onset of virus infection, symptom presentation, and OM. In setting may be ideal for evaluating strategies to prevent the otologic complications of a viral URI, since objective markers theory, this delay can be exploited to reduce the risk of otologic complications by treating the primary virus infection. This of otologic involvement are provoked in relatively high number, there appears to be a window for prophylaxis of the complistrategy has advantages over the prolonged use of antivirals for prophylaxis. Since the target population is circumscribed cation by antiviral treatment after symptom presentation, and an approved relatively safe and effective antiviral, rimantadine, to symptomatic ''at risk'' persons, the required duration of therapy can be limited to the expected period of viral shedding, is available for treatment [9 -11]. The aim of the present stu...
Background: Maintenance of function during cancer treatment is important to older adults. Characteristics associated with pretreatment life-space mobility and changes during non-small cell lung cancer (NSCLC) treatment remain unknown.Methods: This mixed methods cohort study recruited adults age ≥65 with advanced NSCLC starting palliative chemotherapy, immunotherapy, and/or targeted therapy from a Comprehensive Cancer Center, Veterans Affairs, and safety-net clinic. Patients completed geriatric assessments including Life-Space Assessment (LSA) pretreatment and at 1, 2, 4, and 6 months after treatment
9074 Background: The 3rd generation EGFR tyrosine kinase inhibitor (TKI) osimertinib is effective for the treatment of advanced EGFR-mutant (mt) lung adenocarcinoma (LUAD). However, tumor resistance to osimertinib monotherapy invariably occurs. Activation of Aurora Kinase A (AURKA) drives resistance to osimertinib treatment in preclinical models of EGFR-mutant LUAD and is associated with TKI resistance in patients. Alisertib is a selective AURKA inhibitor with an acceptable safety profile established in early phase clinical trials. Methods: We performed a single institution phase Ia clinical trial of alisertib in combination with the 3rd generation EGFR inhibitor osimertinib in patients with metastatic EGFR-mutant LUAD who had experienced disease progression on osimertinib monotherapy (NCT04085315). The primary objective of the study was to determine the safety and tolerability of alisertib in combination with osimertinib in order to define the maximum tolerated dose (MTD) and to identify a recommended phase 2 dose (RP2D). Secondary efficacy endpoints included objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS). Utilizing a 3+3 trial design, patients receiving osimertinib 80 mg daily were treated with alisertib using an intermittent dosing strategy of 20-50 mg twice daily (BID) oral alisertib on days (d) 1-3, 8-11, and 15-17 of a 28-day cycle. Results: A total of 10 patients were treated with osimertinib 80 mg and received at least one dose of alisertib. 6 patients were treated at the 30 mg BID and 4 patients at the 40 mg BID intermittent dosing schedule of alisertib. The most commonly reported adverse events (AEs) were diarrhea (70%), fatigue (60%), alopecia (50%) and neutropenia (50%). All AEs, except neutropenia, were grade 1 or 2. Two patients (20%) experienced grade 3 or grade 4 neutropenia; both patients were treated at the 40 mg BID intermittent dose of alisertib. Intermittent alisertib 30 mg BID was identified as the MTD and RP2D in combination with osimertinib 80 mg daily. The ORR was 10% (1/10) and DCR 70% (7/10), with the majority of patients, 60% (6/10), achieving stable disease (SD). 30% (3/10) experienced progressive disease (PD) as their best response. The median PFS was 9.4 months (2.0 months - N.R.). Conclusions: Intermittent dosing of alisertib 30 mg BID on d1-3, 8-11, and 15-17 of a 28-day cycle in combination with osimertinib 80 mg daily demonstrates an acceptable toxicity profile. Preliminary efficacy analysis suggests that alisertib + osimertinib may result in clinically meaningful disease control in EGFR-mt LUAD patients whose disease is resistant to osimertinib monotherapy. Clinical trial information: NCT04085315.
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